Identification and functional characterization of microRNAs in medulloblastoma

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Abstract

MicroRNAs (miRNAs) have been one of the most contemplated topics in molecular biology studies in the last decade. These short, non-coding RNA molecules (21-25 nucleotides) were showed to play an important role in carcinogenesis with specific expression profiles in distinct cancer types. However, the contribution of deregulated miRNAs to medulloblastoma formation remains poorly understood. Medulloblastoma comprises the most frequent malignant brain tumor in childhood. Despite considerable therapeutic progress in the past decades, medulloblastoma still results in a comparably poor overall survival rate of 60-70%. Among clinical variables, particularly metastatic dissemination at diagnosis, which is present in about 30% of cases, is associated with dismal prognosis. Distinct molecular subgroups with characteristic genomic aberrations and specific gene expression signatures were consistently reported by several groups and shown to be associated with largely different prognosis. This study demonstrates that genome-wide miRNA expression profiling largely reveals molecular subgroups that had previously also been identified by mRNA expression profiling. A robust miRNA signature with 26 miRNAs was found to readily distinguish Sonic hedgehog (SHH) subgroup medullo-blastomas from other subgroups in two independent data sets obtained on different microarray platforms. Retina-specific miRNAs, miR-182, miR-183, and miR-96 were reported to be involved in the tumorigenesis and invasiveness of numerous cancer types, however, not yet studied in medulloblastoma. These miRNAs were the most differentially regulated miRNAs within the 26-miRNA signature, were significantly upregulated in non-SHH medulloblastoma, and were associated with tumor location and metastatic dissemination. Further investigating the functional role of these candidate miRNAs in medulloblastoma cells, this study clearly demonstrates in vitro and in vivo, that overexpression of miR-182 in the context of non-SHH medulloblastoma functionally contributes to the metastatic dissemination of medulloblastoma. This momentous finding regarding the functional role of retina-specific miRNAs in medulloblastoma proves novel insights in the biology of metastatic medulloblastoma. Based on this knowledge, novel targeted treatment approaches may be developed for subgroups with particularly dismal prognosis.